Substance use disorders (SUDs) cost the United States $110 billion each year, while HIV/AIDS approaches $36 billion. Despite extensive prevention and treatment efforts, drug-related deaths remain near historic highs; AIDS is still a leading cause of death among 15-to 24-year olds. Given the inadequate response rates to current prevention and treatment strategies for both SUDs and HIV, improvements are needed to reduce their onset. Future interventions which specifically target cognitive and neural mechanisms known to impact the onset of drug use and risky sexual (leading to HIV acquisition) practices in adolescence would allow for prevention in early, more malleable phases of development. While adolescent behavior provides some clues about motivation for early drug use/sexual behavior, improved understanding of adolescent brain mechanisms underlying the behavior may shed additional light. One process thought to lead to early and problematic drug use/sexual behavior is impairment in risky decision-making. We have shown ventromedial prefrontal activation abnormalities in high-risk youth during risky-decision making, prior to drug experimentation. Specifically, these abnormalities are present when high-risk 10-14-year-olds learn about the negative outcomes of their risky decisions. We speculate that failure of the brain to effectively process, and therefore learn from, a negative outcome may lead adolescents to continue to take drug/sexual behavior risks. Existing imaging-risk studies have defined risk according to a family history of SUD, early substance use, the presence of impulsive/risky behaviors and a combination of these models. Important questions remain: (1) Do brain abnormalities pertaining to risky decision-making in drug-nave adolescents actually predict later risky drug/sexual experimentation? (2) Is there something unique about brain functioning in youth with behavioral manifestations of addiction/sexual behavior risk, depending on whether or not they have parents with SUDs? (3) What are the underlying cognitive processes that lead to abnormal brain response to negative outcomes of risky decisions in high-risk youth? To address these questions we propose to study 2 high-risk groups of non-drug using 11-12- year-olds (those with behavioral risk factors +/- family histories of SUDs) and healthy comparison participants. Brain function of these groups will be assessed cross-sectionally using experimental decision making tasks, along with behavioral assessments of impulse control. Then, youth will then be invited back for interviews about their drug, alcohol and sexual behavior practices over several years. Outcomes of the project will allow for a better understanding of the brain mechanisms that underlie risky-decision making in youth at high risk for SUDs and HIV and the capacity for brain function to predict later drug and high risk sexual behaviors. Ultimately, this information can be translated to novel interventions targeting high-risk youth.